African trypanosomes cause fatal disease in people and their livestock. The tsetse-transmitted protozoa threaten the well-being of 50 million people and exclude cattle from 10 million square kilometers of the humid and subhumid zones of sub-Saharan Africa. African buffalo thrive in the tsetse habitat and are tolerant of infection with all strains of African trypanosomes. These animals maintain parasitemia at a very low or undetectable level and show no signs of disease. Our goal is to elucidate the molecular basis for this resistance characteristic and exploit this knowledge to develop new and sustainable strategies to control trypanosomiasis in humans and their livestock. Our studies show that an African buffalo serum protein of Mr 150,000 selectively inhibits trypanosome glycolysis in vitro resulting in exponential decline in ATP content, a progressive loss of ATP-dependent cellular functions and eventually death of the organisms. We will now characterize the trypanocidal protein (TCP), clone and express complementary deoxyribonucleic acid (cDNA) encoding the protein, identify the binding site for TCP on trypanosomes and ascertain whether binding site-specific antibodies inhibit trypanosome glycolysis. The studies will indicate whether TCP-cDNA or TCP-binding site-specific antibodies have potential to affect prophylactic control of African trypanosomes.